PRECLINICAL GVHD AND MARROW ENGRAFTMENT STUDIES

移植物抗宿主病（GvHD）是异基因骨髓移植（BMT）的主要并发症。 GvHD的风险可以通过骨髓供体和受体的HLA匹配来降低，匹配的兄弟姐妹是主要选择。然而，只有大约30%的患者有HLA匹配的兄弟姐妹，因此必须通过国家骨髓捐献者计划（NMDP）寻找合适的非亲缘HLA匹配的捐献者。GvHD的风险在无关的HLA匹配的患者中仍然相当高，特别是由于MHC II类基因座的遗传变异，其产物可以诱导CD 4 + T细胞应答。骨髓移植排斥反应的预防也是同种异体BMT的关键问题，特别是当涉及MHC II类错配时。作为该计划的一部分，我们将注意力集中在基于结构设计的肽和有机化合物的临床前研究上，这些肽和有机化合物抑制CD 4 + T细胞介导的同种异体反应性。我们将集中精力研究三组抑制剂：（1）D1 CC'环肽（802-2），目前临床试验的先导化合物;（2）设计用于抑制D4结构域中CD 4分子二聚化的新肽;和（3）两种有机化合物（TJU 103和TJU 104），它们被选择为具有阻断D1结构域上的推定结合口袋的能力。 我们将利用的BMT模型包括：（1）MHC半相合B6 D2-> B6 CB（950 cGy）和次要组织相容性抗原（HA）不相合B6 ->BALB.B（850 cGy）的GvHD模型;和2）MHC半倍体相同的B6 CB ATBM-> B6 D2（750 cGy），MHC II类不同的Bm 12 ATBM->B6.Ly5.2（700 cGy），和CD 4-II类限制性的次要HA-不同BALB、B ATBM->B6（700 cGy）的同种异体骨髓移植物排斥的预致敏模型。在这些模型中使用所选的肽和化合物，我们的具体目的是：1）确定802-2、CD 4 D4和有机抑制剂在GvHD和骨髓移植排斥模型中的功效;（2）确定抑制剂的作用机制;和（3）评价用抑制剂治疗后GvHD模型中BMT受体的免疫活性状态。这些研究将为这些新的CD 4抑制剂提供强有力的临床前基础，这些抑制剂可能靶向同种异体反应性细胞，而不会危及随后对感染和白血病的免疫反应。

DESCRIPTION: (Applicant's Description) Graft-versus-host disease (GvHD) is a major complication of allogeneic bone marrow transplantation (BMT). The risk of GvHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, only about 30% of patients have a HLA-matched sibling, and thus must seek suitable unrelated HLA-matched donors through the National Marrow Donor Program (NMDP). The risk of GvHD is still quite high in unrelated HLA-matched patients, particularly due to genetic variants in MHC class II loci, whose products can induce CD4+ T cell responses. The prevention of marrow graft rejection is also a critical issue for allogeneic BMT, particularly when involving MHC class II mismatches. As part of this Program, we have focused our attention on the preclinical investigation of structure-base designed peptides and organic compounds that inhibit CD4+ T cell-mediated alloreactivity. We will concentrate our efforts on three groups of inhibitors: (1) the D1 CC' loop peptide (802-2), the lead compound for the current clinical trial; (2) new peptides designed to inhibit dimerization of CD4 molecules in the D4 domain; and (3) two organic compounds (TJU103, and TJU104) that were selected for their ability to block a putative binding pocket on the D1 domain. The BMT models that we will utilize include: (1) the MHC haploidentical B6D2->B6CB (950 cGy) and minor histocompatibility antigen (HA)-mismatched B6 ->BALB.B (850 cGy) models of GvHD; and 2) the MHC haploidentical B6CB ATBM->B6D2 (750 cGy), MHC Class II-disparate Bm12 ATBM->B6.Ly5.2 (700 cGy), and the CD4-Class II-restricted minor HA-disparate BALB.B ATBM->B6 (700 cGy) presensitized models of allogeneic marrow graft rejection. With the selected peptides and compounds in these models, our specific aims are: 1) to determine the efficacy of the 802-2, CD4 D4, and organic inhibitory agents in the GvHD and marrow graft rejection models; (2) to determine mechanism of action of the inhibitory agents; and (3) to evaluate the immunocompetent status of BMT recipients in the GvHD models after treatment with the inhibitory agents. These studies will provide a strong preclinical basis for these novel CD4 inhibitors that could potentially target alloreactive cells without jeopardizing later immune responses to infection and leukemia.